title: Glutathione- and non-glutathione-based oxidant control in the endoplasmic reticulum.
abstract: The redox-active tripeptide glutathione is an endogenous reducing agent that is found in abundance and throughout the cell. In the endoplasmic reticulum (ER), the ratio of glutathione to glutathione disulfide is lower compared with non-secretory organelles. This relatively oxidizing thiol-disulfide milieu is essential for the oxidative folding of nascent proteins in the ER and, at least in part, maintained by the activity of ER-resident endoplasmic oxidoreductin 1 (Ero1) enzymes that oxidize cysteine side chains at the expense of molecular oxygen. Glutathione disulfide and hydrogen peroxide formed as a consequence of Ero1 activity are widely considered as being inoperative and potentially dangerous by-products of oxidative protein folding in the ER. In contrast to this common view, this Commentary highlights the importance of glutathione- and non glutathione-based homeostatic redox control mechanisms in the ER. Stability in the thiol-disulfide system that prominently includes the protein disulfide isomerases is ensured by the contribution of tightly regulated Ero1 activity, ER-resident peroxidases and the glutathione-glutathione-disulfide redox pair that acts as a potent housekeeper of redox balance. Accordingly, the widely held concept that Ero1-mediated over-oxidation in the ER constitutes a common cause of cellular demise is critically re-evaluated.
authors.affiliation: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstr. 50, CH-4056 Basel, Switzerland. Christian.Appenzeller@unibas.ch
authors.forename: Christian
authors.initials: C
authors.lastname: Appenzeller-Herzog
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism
chemical_list: D016877:Oxidants; D010088:Oxidoreductases; D005978:Glutathione; D019803:Glutathione Disulfide